Nn-di-chloroethylaminobutyrates and preparation thereof



NN-DI-CHLOROETHYLAMINOBUTYRATES AND PREPARATION THEREGF Walter CharlesJoseph Ross, James Lionel Everett, and John James Roberts, London,England, respectively, assignors to National Research DevelopmentCorporation, London, England, a British corporation No Drawing. FiledNov. 9, 1953, Ser. No. 391,134

Claims priority, application Great Britain Nov. 20, 1952 1 Claim. (Cl.260-518) This invention relates to chemotherapeutic agents and has as anobject to provide improved compounds having tumour growth inhibitoryaction.

Bis-chloroethylamines of the general formula RN( CH CH CI) 2 (I) (inwhich R is an aliphatic residue) are well known as cytotoxic agentswhich are capable of arresting the growth of transplanted animal tumours(see Haddow, Brit. Med. Bull. (1947), 4, 422. One disadvantage of thecompounds so far examined which limits their use as chemotherapeuticagents is the non-specificity of their action. They are toxic to alltypes of rapidly proliferating tissue, e.g. bone marrow, gonadal tissueand gastric mucosa, as well as towards neoplastic tissue.

With a view to obtaining substances which would exert a more selectivechemical action we have investigated compounds of the general formula:

CHDaCOOR' Cl HCH N O 2 Q n) in which R is hydrogen or an alkyl group,preferably one containing not more than eight carbon atoms. Thepreferred compound is p-NN-di-(Z-chloroethyl)-aminophenylbutyric acid ofthe formula:

. and this has the following advantages:

(1) This compound exerts a more powerful inhibitory effect upon thegrowth of various experimental tumours in the rat and mouse than dohigher and lower homologues of this series;

(2) At the dosage levels employed, the growth-inhibitory effect is notaccompanied by serious depression of the bone-marrow such as may beinduced by alky1'bis-2- chloroethylamines and many other arylbis-2-chloroethylamines, so far tested;

(3) From the results available, the compound appears outstanding notonly in the series to which it belongs, but in comparison with manyother growth-inhibitory agents studied in the Royal Cancer Hospital overthe past 15 years, in that it can induce complete suppression of thegrowth of the Walker rat carcinoma, and substantial retardation of thegrowth of certain mouse neoplasms, which hitherto had been regarded asmarkedly resistant to chemical treatment. Thus preliminary clinicalinvestigations (over a period of nine months) indicate thatp-NN-di-(Z-chloroethyl) -aminophenylbutyric acid is as effective astriethylenemelamine and methyl-di-Z-chloroethylamine in the treatment ofcertain lymphomas and chronic lymphatic leukaemias and that its use ismore easily controlled and further that in therapeutic doses sideeffects have been negligible. Triethylenernelamine and 2-chloroethylamine are in current use for the treatment of lymphomas andchronic lymphatic leukaemias.

The present invention also includes a process for the manufacture ofcompounds of the general Formula 111 above wherein an alkylNN-di-(Z-hydroxyethyl)-aminophenylbutyrate is treated with phosphorusoxychloride to form an alkyl NN-di-(Z-chloroethyl)-aminophenylbutyratewhich is, if desired, converted by hydrolysis in an acid medium into aNN-di-(2-chloroethyl-aminophenylbutyric acid.

The following examples in which the parts are by weight, illustrate howthe process of the invention may be carried into effect:

(1) 10 parts of methyl p-aminophenylbutyrate (pre pared as by L. D.Freedman and G. O. Doak, J. Amer. Chem. Soc. (1949), 71, 779) wastreated with ethylene oxide (6 parts) and benzene (10 parts) at 150 C.for 18 hours. The resulting methyl P-NN-di-(Z-hYdIOXYfithYD-aminophenylbutyrate (5 parts) was treatedwith POCl (15 parts) andbenzene (100 parts) under reflux for one hour. The methyl p NN di (2chloroethyD- aminophenylbutyrate (8 parts) thus obtained was treatedwith hydrochloric acid (25 parts) by refluxing for 30 minutes. Themixture was cooled, neutralised with ammonia, and acidified with a fewdrops of acetic acid. The resulting p NN di (2 chloroethyl)aminophenylbutyric acid was recrystallised from petro1-ether (GO- C.)M.P. 63 C. Yields, 5 parts. (Found: C, 55.5; H, 6.1. C H O NCI requiresC, 55.3; H, 6.2%.)

The process of the example may be modified by treating themethyl-p-aminophenylbutyrate with ethylene oxide (25 parts) in N aceticacid (50 parts) at room temperature for 4 hours.

(2) 21 parts of p-nitrophenylbutyric acid dissolved in 60 parts of ethylalcohol were treated with 4 parts of acetyl chloride and the mixtureheated under reflux for one hour. and heating continued for a furtherfour hours. After removing the excess of alcohol by distillation theproduct was poured into 10 parts of water and extracted with ether. Theether solution was washed with 2N sodium hydroxide, dried with anhydroussodium sulphate, and

4 parts of acetyl chloride were then added distilled to remove solvent.The resulting ethyl p-nitrophenylbutyrate (21.8 parts) was reduced byshaking an alcoholic solution with Raney-nickel in an atmosphere ofhydrogen. The ethyl p-aminophenylbutyrate (21.2 parts) thus obtained washeated at 150 C. in a sealed tube with 20 parts of dry benzene and 12parts of ethylene oxide for 12 hours. The resulting ethyl p-NN-di-(2-hydroxyethyl)-aminophenylbutyrate (15 parts) was treated with phosphorusoxychloride (15 parts) in benzene (100 parts) by heating under refluxfor one hour. In this way ethylp-NN-di-(Z-chloroethyl)-aminophenylbutyrate was obtained as a colourlessoil (8 parts): it was characterised by hydrolysis to the acid, M.P. 63C.

We claim: p-NN-di-(Z-chloroethyl) -aminophenylbutyrie acid.

References Cited in the file of this patent FOREIGN PATENTS GreatBritain Oct. 30, 1919 Great Britain May 16, 1951 OTHER REFERENCES

